Sequential cleavage of APP by ?- and ?-secretase yields A? peptides that are pathogenic in Alzheimer's Disease (AD), along with AID/AICD, which mediates APP signaling. Some APP and ? -secretase mutations alter the rate of A? production and cause autosomal dominant familial AD (FAD). Given the role of APP processing in AD and APP-mediated functions, modulators of APP cleavage such as BRI2 are biologically relevant and of therapeutic interest. Of note, BRI2 mutations cause autosomal dominant Familial British (FBD) and Familial Danish (FDD) Dementia two AD-like diseases. We have further studied the significance of the BRI2-APP interaction and found that: 1) BRI2 inhibits APP processing and A2 generation;2) BRI2 mutants that cause FBD and FDD are poor inhibitors of APP processing. Thus, our working hypothesis is that: A) BRI2 is a competitive inhibitor of APP cleavage by secretases;B) BRI2 regulates AD pathogenesis;C) FBD and FDD BRI2 mutants exacerbate the progression of AD, and dis- regulation of APP processing may participate in FDD and FBD pathogenesis. This grant has three Aims in which we propose to test these hypotheses. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the most common cause of dementia in the world. It is estimated that ~1% of humans aged 60-64 years have AD, increasing steadily to as many as 35%-40% after age 85. AD is caused by the formation of plaques in the brain. These plaques impair the function of neuronal cells and, eventually, cause death of these cells. When the damage is large enough, dementia ensues. These senile plaques are formed by accumulation of a small molecule. Much of the efforts from scientists and industry are concentrated on findings drugs capable of preventing formation of these plaques or promoting the removal of this noxious material. This project application aims to study a protein that can diminish the formation of this toxic substance. We hope that our studies will translate into a program to develop drug for altering the course of the disease versus simply treating the symptoms like all of the approved drugs for AD currently are.